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Background: Administrative burdens have been identified as a major issue impacting patient care, professional practice, and the overall efficiency of healthcare systems. The aim of this study is to assess the administrative burden faced by Italian hematologists., Methods: A cross-sectional survey that included both closed-ended quantitative questions and open-ended free text answer options was administered to 1,570 hematologists working with malignancies and members of Italian GIMEMA Foundation - Franco Mandelli ONLUS and the Italian Linfomi Foundation (FIL). The survey was conducted online from May 24 to June 30, 2023. Descriptive statistics were computed for the quantitative data to clearly summarize the responses and descriptive analysis of free text responses was carried out., Results: Surveyed hematologists spend an average of 47.07% of their time on administrative tasks, with 63.22% (n = 110) of respondents reporting spending at least half of their time on these activities. More than half (57.47%, n = 100) reported that "Patient care" is the medical task most affected by a lack of time. Additionally, 55.17% (n = 96) reported experiencing burnout in the past 6 months, with filling out "Forms" being identified as the top contributing administrative task by 27.59% (n = 48) of respondents, followed by "Scheduling" (24.71%, n = 43) and "Managing IT system failures" (21.84%, n = 38). Nearly half of the surveyed hematologists (45.40%, n  =  = 79) identified patient care as the top priority requiring more time., Conclusions: The study confirms that the administrative workload of hematologists has a significant impact on patient care, communication, and burnout risk, reducing the time available for patient care, leading to exhaustion and concern about clinical errors., (© 2024 The Authors.)

Chronic Kidney Disease (CKD) is a clinical condition characterized by the progressive loss of kidney function. 10% of the world's population is affected by this condition, which represents the fifth leading cause of death globally. Furthermore, CKD is associated with increased risk of fatal and non-fatal cardiovascular events, and progression to end-stage renal disease. Over the last twenty years, an exponential growth in its prevalence and incidence has been observed. For this reason, various drugs have been developed and implemented in clinical practice, with various mechanisms, with the aim of reducing and minimizing this dramatic "cardio-renal" risk. These include SGLT2 inhibitors, mineralocorticoid receptor antagonists, and endothelin receptor antagonists. However, a large proportion of CKD patients do not respond sufficiently to these treatments. GLP-1 receptor agonists represent a class of antidiabetic and nephroprotective drugs that are very promising in improving the prognosis of patients with CKD, especially if associated with one of the above-mentioned classes. In this article, we discuss the direct and indirect mechanisms through which one of the GLP-1 agonists, semaglutide, ensures nephro- and cardioprotection in patients with CKD and type 2 diabetes., (Copyright by Società Italiana di Nefrologia SIN, Rome,Italy.)

This review aims to analyze the recent studies about prebiotics and precision biotics, as alternatives to animal growth promoters. These substances improve intestinal health, growth performance and poultry environmental impact. Prebiotics are insoluble fibers, that have no nutritive value, but they promote the growth of positive bacteria, increase the nutrients absorption and modulate the immune response. Instead, precision biotics are carbohydrates with glycosidic linkages, which interact with gut bacteria metabolism, reducing the excretion of nitrogen and consequentially, the poultry environmental impact. In the last years, different studies were published in this field, and for this reason, it is necessary to organize the results found. It was shown that mannan-oligosaccharides and β-glucans increase ileal nutrient digestibility, nitrogen retention and antibodies titers. Inulin, arabinoxylans-derived oligosaccharides, and galacto-oligosaccharides improved intestinal morphology, arranging for a larger absorption surface area. It was reported that prebiotics enhance the colonization of positive bacteria and can reduce the count of Campylobacter colonies. Furthermore, xylo-oligosaccharides are often used in animal feed, due to their ability to form organic acids, which decompose noxious substances, improving litter quality, and consequentially, reducing the environmental impact. Litter quality is a relevant aspect for ammonia emissions and for animal welfare. Whether the litter quality is poor, footpad dermatitis increase, worsening animal welfare and increasing nitrogen emissions to air. Precision biotics select metabolic pathways to modulate amino acid degradation, reintegrating the nitrogen discarded, and reducing the ammonia level in litter. It was also reported an improvement of growth performance and a better animal welfare. In conclusion, prebiotics and precision biotics can have positive effects on animal performance and welfare, and they can be a new strategy to reduce the environmental impact of chickens' farms., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.)

Introduction: The myoelectric control strategy, based on surface electromyographic signals, has long been used for controlling a prosthetic system with multiple degrees of freedom. Several methods classify gestures and force levels but the simultaneous real-time control of hand/wrist gestures and force levels did not yet reach a satisfactory level of effectiveness., Methods: In this work, the hierarchical classification approach, already validated on 31 healthy subjects, was adapted for the real-time control of a multi-DoFs prosthetic system on 15 trans-radial amputees. The effectiveness of the hierarchical classification approach was assessed by evaluating both offline and real-time performance using three algorithms: Logistic Regression (LR), Non-linear Logistic Regression (NLR), and Linear Discriminant Analysis (LDA)., Results: The results of this study showed the offline performance of amputees was promising and comparable to healthy subjects, with mean F1 scores of over 90% for the "Hand/wrist gestures classifier" and 95% for the force classifiers, implemented with the three algorithms with features extraction (FE). Another significant finding of this study was the feasibility of using the hierarchical classification strategy for real-time applications, due to its ability to provide a response time of 100 ms while maintaining an average online accuracy of above 90%., Discussion: A possible solution for real-time control of both hand/wrist gestures and force levels is the combined use of the LR algorithm with FE for the "Hand/wrist gestures classifier", and the NLR with FE for the Spherical and Tip force classifiers., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Leone, Mereu, Gentile, Cordella, Gruppioni and Zollo.)

Objectives: HCQ and AZA are used to control disease activity and reduce risk of flare during pregnancy in patients with SLE. The aim of this study was to determine the outcomes of children born to mothers with SLE exposed to HCQ or AZA during pregnancy and breast-feeding., Methods: Women attending UK specialist lupus clinics with children ≤17 years old, born after SLE diagnosis, were recruited to this retrospective study. Data were collected using questionnaires and from clinical record review. Factors associated with the outcomes of low birth weight and childhood infection were determined using multivariable mixed-effects logistic regression models., Results: We analysed 284 live births of 199 mothers from 10 UK centres. The first pregnancies of 73.9% of mothers (147/199) were captured in the study; (60.4%) (150/248) and 31.1% (87/280) children were exposed to HCQ and AZA, respectively. There were no significant differences in the frequency of congenital malformations or intrauterine growth restriction between children exposed or not to HCQ or AZA. AZA use was increased in women with a history of hypertension or renal disease. Although AZA was associated with low birth weight in univariate models, there was no significant association in multivariable models. In adjusted models, exposure to AZA was associated with increased reports of childhood infection requiring hospital management [odds ratio 2.283 (1.003, 5.198), P = 0.049]., Conclusions: There were no significant negative outcomes in children exposed to HCQ in pregnancy. AZA use was associated with increased reporting of childhood infection, which warrants further study., (© The Author(s) 2022. Published by Oxford University Press on behalf of the British Society for Rheumatology.)

Background: In the field of myoelectric control systems, pattern recognition (PR) algorithms have become always more interesting for predicting complex electromyography patterns involving movements with more than 2 Degrees of Freedom (DoFs). The majority of classification strategies, used for the prosthetic control, are based on single, hierarchical and parallel linear discriminant analysis (LDA) classifiers able to discriminate up to 19 wrist/hand gestures (in the 3-DoFs case), considering both combined and discrete motions. However, these strategies were introduced to simultaneously classify only 2 DoFs and their use is limited by the lack of online performance measures. This study introduces a novel classification strategy based on the Logistic Regression (LR) algorithm with regularization parameter to provide simultaneous classification of 3 DoFs motion classes., Methods: The parallel PR-based strategy was tested on 15 healthy subjects, by using only six surface EMG sensors. Twenty-seven discrete and complex elbow, hand and wrist motions were classified by keeping the number of electromyographic (EMG) electrodes to a bare minimum and the classification error rate under 10 %. To this purpose, the parallel classification strategy was implemented by using three classifiers one for each DoF: the "Elbow classifier", the "Wrist classifier", and the "Hand classifier" provided the simultaneous control of the elbow, hand, and wrist joints, respectively., Results: Both the offline and real-time performance metrics were evaluated and compared with the LDA parallel classification results. The real-time recognition results were statistically better with the LR classifier with respect to the LDA classifier, for all motion classes (elbow, hand and wrist)., Conclusions: In this paper, a novel parallel PR-based strategy was proposed for classifying up to 3 DoFs: three joint classifiers were employed simultaneously for classifying 27 motion classes related to the elbow, wrist, and hand and promising results were obtained., (© 2022. The Author(s).)

The evolution of technological and surgical techniques has made it possible to obtain an even more intuitive control of multiple joints using advanced prosthetic systems. Targeted Muscle Reinnervation (TMR) is considered to be an innovative and relevant surgical technique for improving the prosthetic control for people with different amputation levels of the limb. Indeed, TMR surgery makes it possible to obtain reinnervated areas that act as biological amplifiers of the motor control. On the technological side, a great deal of research has been conducted in order to evaluate various types of myoelectric prosthetic control strategies, whether direct control or pattern recognition-based control. In the literature, different control performance metrics, which have been evaluated on TMR subjects, have been introduced, but no accepted reference standard defines the better strategy for evaluating the prosthetic control. Indeed, the presence of several evaluation tests that are based on different metrics makes it difficult the definition of standard guidelines for comprehending the potentiality of the proposed control systems. Additionally, there is a lack of evidence about the comparison of different evaluation approaches or the presence of guidelines on the most suitable test to proceed for a TMR patients case study. Thus, this review aims at identifying these limitations by examining the several studies in the literature on TMR subjects, with different amputation levels, and proposing a standard method for evaluating the control performance metrics.

TB is still a major public health problem and a threat to global health security. In Italy, TB control is consistent with the WHO global strategy, in which the role of prevention and, within it, contacts tracing and their management are emphasized. In this work, a protocol for the correct and homogeneous management of TB cases, at local level, is described in all its phases, from reporting to contacts management. The containment of the diffusion of the infection and the prevention of new outbreaks depend on the immediate identification of the index case and the proper performance of the epidemiological investigation. For this reason, the translation of scientific evidence into Recommendations and Guidelines is essential, and of these into operational protocols for the local level, with a clear indication of actions and responsibilities.

Surface electromyography (sEMG) signals represent a promising approach for decoding the motor intention of amputees to control a multifunctional prosthetic hand in a non-invasive way. Several approaches based on proportional amplitude methods or simple thresholds on sEMG signals have been proposed to control a single degree of freedom at time, without the possibility of increasing the number of controllable multiple DoFs in a natural manner. Myoelectric control based on PR techniques have been introduced to add multiple DoFs by keeping low the number of electrodes and allowing the discrimination of different muscular patterns for each class of motion. However, the use of PR algorithms to simultaneously decode both gestures and forces has never been studied deeply. This paper introduces a hierarchical classification approach with the aim to assess the desired hand/wrist gestures, as well as the desired force levels to exert during grasping tasks. A Finite State Machine was introduced to manage and coordinate three classifiers based on the Non-Linear Logistic Regression algorithm. The classification architecture was evaluated across 31 healthy subjects. The "hand/wrist gestures classifier," introduced for the discrimination of seven hand/wrist gestures, presented a mean classification accuracy of 98.78%, while the "Spherical and Tip force classifier," created for the identification of three force levels, reached an average accuracy of 98.80 and 96.09%, respectively. These results were confirmed by Linear Discriminant Analysis (LDA) with time domain features extraction, considered as ground truth for the final validation of the performed analysis. A Wilcoxon Signed-Rank test was carried out for the statistical analysis of comparison between NLR and LDA and statistical significance was considered at p < 0.05. The comparative analysis reports not statistically significant differences in terms of F1Score performance between NLR and LDA. Thus, this study reveals that the use of non-linear classification algorithm, as NLR, is as much suitable as the benchmark LDA classifier for implementing an EMG pattern recognition system, able both to decode hand/wrist gestures and to associate different performed force levels to grasping actions.

Introduction: Cytomegalovirus (CMV) infection represents a common cause of morbidity and mortality in kidney transplant recipients (KTR). The NF-kB signaling pathway is highly involved in the pathogenesis of CMV infection. The -94ins/delATTG functional polymorphism in the promoter of NFKB1 has been associated with low intracellular levels of the protein and high incidence of inflammatory and autoimmune disease. In this study, we evaluated the association of this NFKB1 polymorphism with the risk of CMV infection., Methods: CMV infection was defined as virus isolation or detection of viral antigens or nucleic acid in any body fluid or tissue specimen. Using Cox regression and survival analysis, we analyzed the association between the polymorphism and CMV infection as well as recurrence in the first 12 months after transplantation., Results: We analyzed the -94ins/delATTG NFKB1 polymorphism of 189 KTRs. The 65% of CMV infections occurred in ins/ins group. Survival free from CMV infection was 54.7% for ins/ins group and 79.4% for deletion carriers one year after transplantation (P < 0.0001). At multivariate regression, deletion carriers showed a lower risk of CMV infection and recurrence with respect to ins/ins KTRs (HR = 0.224 P = 0.0002; HR = 0.307, P = 0.012, respectively)., Conclusions: In conclusion, pretransplantation screening for NFKB1 -94ins/delATTG polymorphism may predict CMV infection and improve the management of patients at higher risk of infection in the post-transplant period., (© 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: Clinical studies have demonstrated that, after renal transplantation (TX), testosterone deficiency (TD) at the time of the procedure is independently associated with lower survival of the patient and graft. However, data between TD and the functional CAG polymorphism of the androgen receptor promoter (AR) are discordant. We investigated the prevalence of TD and its association with body composition, biochemical parameters, the Aging Males' Symptoms rating scale (AMS) domains and AR polymorphism., Methods: In 112 TX patients, we assessed the AMS, biochemical/hormonal (FSH/LH/TT) anthropometric/bioimpedance analysis parameters, and AR CAG polymorphism of AR by gene sequencing., Results: Median values of total testosterone (TT) were 340 ng/dl and 52% of TX patients were affected by TD. Significant correlations between TT and FSH and FSH and LH (p = 0.005, p < 0.0001, respectively) were found. TD patients had lower estimated glomerular filtration rate (eGFR) and hemoglobin (Hb) (p = 0.034, p = 0.022 respectively) and showed higher values of C-reactive protein (p = 0.023) and fat tissue index/adipose tissue mass (p = 0.034 and p = 0.021, respectively), and lower values of serum albumin (p = 0.003) and high-density lipoprotein-cholesterol (p = 0.038) levels. Significant differences were found in the number of patients on mammalian target of rapamycin inhibitors immunosuppressant therapy (p = 0.045). Logistic regression analysis did not show any correlation between age, AMS scores, TT or CAG repeat length, gonadotropins, time of the transplant, and dialysis., Conclusions: Our results suggest that in TX recipients an appropriate sexual hormonal evaluation should be performed, as we found a high prevalence of TD. However, further studies are needed to clarify the association between TD and patient and graft survival.

Aim: To investigate same day repeated measures and diurnal variation of arterial stiffness, cardiac output (CO), stroke volume (SV) and total peripheral resistance (TPR) during the third trimester of normal pregnancy., Methodology: Pulse wave velocity (PWV) and augmentation index (AIx) were recorded using the Arteriograph, while CO, SV and TPR were recorded using noninvasive cardiac output monitoring. The measurements were obtained in the third trimester of pregnancy from 21 healthy pregnant women at four time points (morning, afternoon, evening and midnight) over a 24-h period. Triplicate measurements of 67 women were obtained at 5-min intervals to assess repeatability between measurements within a patient., Results: Diurnal measurements of arterial stiffness for brachial AIx, aortic AIx and PWV were not statistically significantly different at any of the four time points. Estimated means (SD) for PWV at the four stated time points were 7.81 (2.05), 8.45 (1.68), 7.87 (1.74) and 7.64 m/s (1.15), respectively (P = 0.267). Estimates for AIx at those time points were 10.22 (15.62), 4.44 (10.07), 6.49 (10.92) and 8.40% (8.16), respectively (P = 0.295). Similarly, mean arterial pressure, SV, SV index and TPR did not show any evidence of diurnal variation. However, we observed that the mean CO, cardiac index (CI) and heart rate (HR) varied from morning to midnight; the mean CO, HR and CI increased significantly in the afternoon compared with the corresponding mean morning measurements in a similar fashion to HR. Mean (SD) CO estimates at the four stated time points were 5.90 (1.33), 6.38 (1.49), 6.18 (1.43) and 5.80 ml/min (1.19), respectively, (P < 0.001), whereas mean CI estimates were 3.65 (0.58), 3.93 (0.68), 3.81 (0.65), and 3.57 (0.48), respectively, (P < 0.001), and mean HR estimates were 95 (12), 98 (13), 95 (12) and 88 (12.98), respectively (P < 0.001). Triplicate measurements of 61 women in our repeatability study showed moderate-to-high correlation between observations on the same woman for all Arteriograph and noninvasive cardiac output monitoring variables (estimates of intraclass correlation ranged from 0.49 to 0.91)., Conclusion: With the exception of CO, CI and HR which showed a diurnal variation, measurements of most haemodynamic parameters did not change significantly from morning to midnight, suggesting there was no evidence of systematic differences in the mean values of these variables at these time points. Multiple consecutive noninvasive measurements of vascular stiffness, CO, SV and TPR were highly correlated confirming repeatability of measurements in the third trimester of uncomplicated pregnancy, so these haemodynamic measurements do not need to be undertaken at a specific time period of the day.

Pitt-Hopkins syndrome is a neurodevelopmental disorder characterized by severe intellectual disability and a distinctive facial gestalt. It is caused by haploinsufficiency of the TCF4 gene. The TCF4 protein has different functional domains, with the NLS (nuclear localization signal) domain coded by exons 7-8 and the bHLH (basic Helix-Loop-Helix) domain coded by exon 18. Several alternatively spliced TCF4 variants have been described, allowing for translation of variable protein isoforms. Typical PTHS patients have impairment of at least the bHLH domain. To which extent impairment of the remaining domains contributes to the final phenotype is not clear. There is recent evidence that certain loss-of-function variants disrupting TCF4 are associated with mild ID, but not with typical PTHS. We describe a frameshift-causing partial gene deletion encompassing exons 4-6 of TCF4 in an adult patient with mild ID and nonspecific facial dysmorphisms but without the typical features of PTHS, and a c.520C > T nonsense variant within exon 8 in a child presenting with a severe phenotype largely mimicking PTHS, but lacking the typical facial dysmorphism. Investigation on mRNA, along with literature review, led us to suggest a preliminary phenotypic map of loss-of-function variants affecting TCF4. An intragenic phenotypic map of loss-of-function variants in TCF4 is suggested here for the first time: variants within exons 1-4 and exons 4-6 give rise to a recurrent phenotype with mild ID not in the spectrum of Pitt-Hopkins syndrome (biallelic preservation of both the NLS and bHLH domains); variants within exons 7-8 cause a severe phenotype resembling PTHS but in absence of the typical facial dysmorphism (impairment limited to the NLS domain); variants within exons 9-19 cause typical Pitt-Hopkins syndrome (impairment of at least the bHLH domain). Understanding the TCF4 molecular syndromology can allow for proper nosology in the current era of whole genomic investigations., (Copyright © 2017. Published by Elsevier Masson SAS.)

Cardiovascular (CV) disease is the leading cause of death in chronic kidney disease (CKD) and end-stage renal disease (ESRD). A key driver in this pathology is increased aortic stiffness, which is a strong, independent predictor of CV mortality in this population. Aortic stiffening is a potentially modifiable biomarker of CV dysfunction and in risk stratification for patients with CKD and ESRD. Previous work has suggested that therapeutic modification of aortic stiffness may ameliorate CV mortality. Nevertheless, future clinical implementation relies on the ability to accurately and reliably quantify stiffness in renal disease. Pulse wave velocity (PWV) is an indirect measure of stiffness and is the accepted standard for non-invasive assessment of aortic stiffness. It has typically been measured using techniques such as applanation tonometry, which is easy to use but hindered by issues such as the inability to visualize the aorta. Advances in cardiac magnetic resonance imaging now allow direct measurement of stiffness, using aortic distensibility, in addition to PWV. These techniques allow measurement of aortic stiffness locally and are obtainable as part of a comprehensive, multiparametric CV assessment. The evidence cannot yet provide a definitive answer regarding which technique or parameter can be considered superior. This review discusses the advantages and limitations of non-invasive methods that have been used to assess aortic stiffness, the key studies that have assessed aortic stiffness in patients with renal disease and why these tools should be standardized for use in clinical trial work.

Background: Cerebral sinovenous thrombosis is unusual in the asphyxiated cooled infants, but reliable data regarding the incidence of this comorbidity are lacking. We assessed the incidence of sinovenous thrombosis in a population of asphyxiated cooled infants by performing routine brain magnetic resonance venography., Methods: All asphyxiated infants who underwent therapeutic cooling at our institution completed brain magnetic resonance venography after rewarming. Assessing the incidence of cerebral sinovenous thrombosis was the primary goal. Secondary analyses included group comparisons for laboratory tests and monitored parameters, relationship between variables, logistic regression models, and receiver operating characteristic curve for cerebral sinovenous thrombosis prediction., Results: Cerebral sinovenous thrombosis was detected in 10 of 37 infants (27%), most commonly affecting the superior sagittal sinus (eight of ten). These infants manifested higher blanket (P < 0.001) and lower esophageal temperatures (P = 0.006), lower platelet counts (P = 0.045), and received more red blood cell transfusions (P = 0.038) than the cooled infants without thrombosis. Blanket temperature was independently associated with cerebral sinovenous thrombosis (P = 0.049), and 32°C/hour was the optimal cutoff value to predict the event (sensitivity, 90%; specificity, 88.5%)., Conclusions: High incidence or cerebral sinovenous thrombosis in neonates treated with therapeutic hypothermia suggests that magnetic resonance venography may be reasonable in many of these children. High blanket temperature may be one variable that helps identify patients at higher risk., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Subclinical rejection (SCR) has been variably associated with reduced graft survival, development and progression of interstitial fibrosis/tubular atrophy and chronic allograft nephropathy, but data are controversial concerning SCR treatment in terms of graft survival improvement. In this single-center retrospective study, we enrolled 174 adult kidney transplant recipients with a protocol biopsy performed at 30 days after transplantation to evaluate the incidence rate and risk factors for early SCR and its impact on 10-year graft survival. Five patients showed primary non function and were excluded. Among 159/169 (94.08 %) patients with stable graft function who underwent protocol biopsy, 17 (10.7 %) showed signs of SCR and were treated with low-dose intravenous (i.v.) steroids. Ten patients showed functional impairment, 8 (4.73 %) resulting as acute rejection. At multivariate analysis, donor age [odds ratio (OR) 1.04, 95 % confidence interval (CI) 1.01-1.09], and delayed graft function (DGF) (OR 1.08, 95 % CI 1.03-1.12) were significantly associated with SCR. The 10-year graft survival rate in the SCR group was similar to that in the normal-findings group (76.5 vs. 74.9 % respectively; p = 0.61). At multivariate Cox regression, acute [hazard ratio (HR) 5.22, 95 % CI 1.70-16.01], but not sub-clinical, rejection was independently associated with long-term graft failure. In conclusion, early protocol biopsy is a useful and safe tool to detect early SCR which seems not to affect the long-term survival. We suggest that this could be, probably, linked to early SCR treatment with low dose i.v. steroids.

The pathogenetic role of adiponectin (ADPN) in kidney failure is not yet elucidated, since in vitro and in vivo studies have demonstrated that ADPN exerts both anti-inflammatory and pro-inflammatory effects. Starting from our previous findings demonstrating that HK-2 cells express and secrete ADPN, in this study we investigated the autocrine role of ADPN in tubular inflammatory damage induced by lipopolysaccharide (LPS) and the underlying molecular mechanisms. Firstly, we observed that short-term exposure to LPS enhanced ADPN protein expression as well as the adiponectin receptor ADIPOR1 mRNA content together with its signaling pathway downstream, pAMPK/pERK/pJNK, whose up-regulation status was reversed when ADPN gene knockdown occurred. Interestingly, in the same experimental conditions, we observed that ADPN mediated the nuclear translocation of the transcription factors nuclear factor kappa B (NFkB) and pcFos/pcJun (activator protein 1, AP-1), both induced by the pJNK pathway and involved in tumor necrosis factor (TNF)-α transactivation. Indeed, by transient transfection assay, we observed that the LPS-induced increase of TNF-α promoter activity was abrogated in cells pretreated with the inhibitors of NFkB and AP-1. Collectively our results suggest that in HK-2 cells, ADPN produced upon LPS stimulus could worsen the inflammatory damage in an autocrine-dependent manner.

To propose a clinical prognostic index for death and heart failure in patients with ischemic cardiomyopathy implanted with an ICD. This prospective study included 192 consecutive patients (age 68 ± 10) recruited from 2004 to 2009 and implanted with an ICD for MADIT II criteria. All patients performed 24-h ambulatory blood pressure monitoring after discharge and common haematological samples. The prognostic index (PI) was built according to the formula: 120 - age + mean 24 h systolic blood pressure--(creatinine 9 10). Other variables were assessed: EF, haemoglobin concentration, mean 24 h heart rate and diastolic blood pressure, sodium level, pacing mode and diabetes. Non-arrhythmic cardiac death and new hospitalizations for heart failure during 1-year follow-up were the combined end point. A total of 48 events (25%) occurred during the follow-up: 7 cardiac deaths and 41 hospitalizations for acute heart failure. Cox proportional hazards model showed that PI was the only predictor of events (HR = 0.96; CI 95% 0.944–0.976, p < 0.0001). ROC curve showed that PI best cut-off was 144, with AUC 0.79, p < 0.0001; sensitivity 77%, specificity 74%, positive predictive value 50%, negative predictive value 90%. PI was predictive of events in a clinical setting where EF had no predictive value. PI works according to the rule ‘‘the lower the worse’’. The high negative predictive value (90%) of PI allows to identify subjects at lower risk for death and heart failure. PI can be a practical tool to stratify risk in ischemic cardiomyopathy.

Clinical studies showed that renal expression and serum levels of nerve growth factor (NGF) are increased in renal diseases characterized by progressive fibrosis, a pathologic process in which TGF-β1 mediates most of the key events leading to tubular epithelial-mesenchymal transition (EMT). However, the pathogenic role of high NGF levels has not yet been elucidated. In this study, we found that in tubular renal cells, HK-2, NGF transcriptionally up-regulated TGF-β1 expression and secretion and enhanced cell motility by activating EMT markers via its receptors, TrkA and p75(NTR). Interestingly, we observed that TGF-β1-SMAD pathway activation and the up-regulation of EMT markers NGF-induced were both prevented when knockdown of TGF-β1 gene occurred and that the pretreatment with an antibody anti-NGF reversed the nuclear translocation of pSMAD3/SMAD4 complex. Collectively, our results demonstrated that NGF promotes renal fibrosis via TGF-β1-signaling activation, suggesting that in kidney diseases high NGF serum levels could contribute to worsen renal fibrosis.

Background: Data on serum soluble Klotho levels in chronic kidney disease are contradictory and even less is known after renal transplantation. Experimental studies demonstrated that recombinant human erythropoietin (rhEPO) treatment mitigates Klotho reduction caused by renal damage. Therefore, this study aimed to determine serum Klotho levels in a cohort of kidney transplant recipients (KTR) and to evaluate whether rhEPO treatment can modulate, in vivo and in vitro, soluble Klotho., Methods: 117 KTR and 22 healthy subjects (HS) were enrolled. In 17 KTR, rhEPO was discontinued for 5 weeks and Klotho levels were compared to 34 propensity score-matched controls. Moreover, we evaluated Klotho mRNA expression and protein secretion in HK-2 tubular cells treated with cyclosporin A (CyA) and rhEPO, alone or in combination., Results: Serum Klotho levels in KTR were significantly higher than in HS (0.68 vs. 0.37, p = 0.002) and significantly associated with estimated glomerular filtration rate (r = -0.378, p = 0.003) and fibroblast growth factor 23 (r = -0.307, p < 0.0001). After 5 weeks of rhEPO discontinuation, treated KTR showed a sharper reduction of Klotho levels than controls (-0.56 vs. -0.11 ng/ml, p < 0.0001). In HK-2 cells CyA treatment induced a Klotho down-regulation that was mitigated by rhEPO pre-treatment. In the same experimental conditions, our results revealed that cells treated with CyA + rhEPO secreted higher soluble Klotho levels than those exposed to CyA or rhEPO alone., Conclusions: Our results demonstrate that KTR have higher serum Klotho levels than HS and that rhEPO treatment modulates these concentrations, suggesting a link between rhEPO and soluble Klotho in KTR.

Nerve growth factor is a neurotrophin that promotes cell growth, differentiation, survival and death through two different receptors: TrkA(NTR) and p75(NTR). Nerve growth factor serum concentrations increase during many inflammatory and autoimmune diseases, glomerulonephritis, chronic kidney disease, end-stage renal disease and, particularly, in renal transplant. Considering that nerve growth factor exerts beneficial effects in the treatment of major central and peripheral neurodegenerative diseases, skin and corneal ulcers, we asked whether nerve growth factor could also exert a role in Cyclosporine A-induced graft nephrotoxicity. Our hypothesis was raised from basic evidence indicating that Cyclosporine A-inhibition of calcineurin-NFAT pathway increases nerve growth factor expression levels. Therefore, we investigated the involvement of nerve growth factor and its receptors in the damage exerted by Cyclosporine A in tubular renal cells, HK-2. Our results showed that in HK-2 cells combined treatment with Cyclosporine A + nerve growth factor induced a significant reduction in cell vitality concomitant with a down-regulation of Cyclin D1 and up-regulation of p21 levels respect to cells treated with Cyclosporine A alone. Moreover functional experiments showed that the co-treatment significantly up-regulated human p21promoter activity by involvement of the Sp1 transcription factor, whose nuclear content was negatively regulated by activated NFATc1. In addition we observed that the combined exposure to Cyclosporine A + nerve growth factor promoted an up-regulation of p75 (NTR) and its target genes, p53 and BAD leading to the activation of intrinsic apoptosis. Finally, the chemical inhibition of p75(NTR) down-regulated the intrinsic apoptotic signal. We describe two new mechanisms by which nerve growth factor promotes growth arrest and apoptosis in tubular renal cells exposed to Cyclosporine A.

Background: Adiponectin (ADPN) is predominantly produced by adipose tissue, and high ADPN levels have been detected in patients affected by proteinuric glomerulonephritis. In this study we investigate whether human tubular epithelial cells express and secrete ADPN., Methods: In human proximal tubular epithelial cells, HK-2, ADPN mRNA was evaluated by real-time PCR assay, while protein expression levels were measured by Western blot analysis and immunofluorescence assay. Moreover, renal ADPN distribution was assessed by immunohistochemical analysis of kidney biopsy samples from healthy patients. Finally, by ELISA, we measured ADPN concentrations in culture media of HK-2 cells treated with 10 µg/mL lipopolysaccharide (LPS)., Results: Our analyses revealed that HK-2 cells express ADPN both in terms of mRNA and protein. These results were confirmed by the observed cytoplasmatic HK-2 intense immunoreactivity for ADPN antibody and by immunohistochemical analysis showing a diffuse ADPN distribution in normal kidney tissue. Furthermore, we observed that tubular cells secrete ADPN in the basal condition and, more interestingly, that this secretion significantly increases (p<0.05) upon LPS treatment in a time-dependent manner. Finally, immunohistochemical analysis of kidney biopsy samples obtained from patients affected by membranous and rapidly progressive glomerulonephritis showed a similar pattern of ADPN staining to that observed in healthy controls., Conclusions: Our study demonstrates for the first time that renal tubular cells express and secrete ADPN, and their concentration increases upon inflammatory stimulus. These results suggest that in renal inflammatory diseases, tubular cells may contribute to the increase in circulating ADPN levels, triggering a feedback response in order to self-mitigate the inflammatory process.

Aim: To compare the rates of success and complications of two different methods of access into the common bile duct (CBD)., Methods: Between October 2007 and November 2008, 173 consecutive patients (71 men, 102 women, mean age 68.6 years) requiring endoscopic retrograde cannulation of the papilla and endoscopic treatment were studied. In the first 88 patients CBD cannulation was performed through supra-papillary fistulotomy (group F); in the following 85 patients standard cannulation was performed through the Oddi sphincter (group S). Indications for the procedure were: choledocholithiasis, biliary obstruction, postoperative leak, sclerosing cholangitis, and Mirizzi's syndrome., Results: Deep CBD cannulation was successful in 85/88 patients (96.5%) in group F vs 60/85 patients (70.6%) in group S (P < 0.0001). The remaining 25 group S patients in whom cannulation failed were shifted to fistulotomy. Fistulotomy was successful in 21/25 patients (84%). As for complications, hyperamilasemia occurred in 7 (7.9%) group F patients vs 7 (8.2%) group S patients (P = NS); mild pancreatitis in 1 (1.1%) group F patient vs 5 (5.8%) group S patients (P = NS); bleeding in 3 (3.4%) group F patients vs 3 (3.5%) group S patients (P = NS)., Conclusion: Needle-knife fistulotomy should represent either the first approach to therapeutic cannulation or rescue therapy after unsuccessful standard cannulation.

A case of retrobulbar monolateral optic neuritis due to disseminated Cryptococcosis in a 32-year-old man with a new diagnosis of AIDS is described in the era of combination antiretroviral therapy (cART). The patient presented a monolateral rapid visual loss on day 7 of a liposomal amphotericin B treatment. Neuroradiological imaging showed the presence of retrobulbar neuritis. After starting ART and intravenous metilprednisolone 1 g daily for 3 days, we assisted to a progressive improvement of visual acuity. At 3 months of follow-up, complete clinical resolution was obtained. In this case, in the presence of effective antiretroviral and antifungal treatment, a short course of metilprednisolone was a safe therapy.

Background: In patients with acute stroke, the hyperdense middle cerebral artery (MCA) and internal carotid artery (ICA) signs on CT scans are markers of early ischemia, but their prognostic implications remain unclear.The aims of this prospective study were to assess: (1) the occurrence rate of hyperdense MCA and/or ICA in patients admitted for acute ischemic stroke; (2) the risk factors for hyperdense MCA and/or ICA; (3) the correlation between hyperdense MCA and/or ICA and functional outcome at 3 months., Methods: Consecutive patients admitted with ischemic stroke between 1 January 2006 and 30 June 2010 were included in this prospective single-centre cohort study., Results: 1,010 patients (mean age 71.9 years; 56.7% males) were included in the study. Among these patients, 148 (14.7%; mean age 71.2 years; 52% males) had hyperdense MCA and/or ICA. Overall, 163 patients (16.1%) had a final infarct covering more than one third of the MCA territory. Seventy-eight of 148 patients (52.7%) with hyperdense MCA and/or ICA had an infarct involving more than one third of the MCA territory compared to 85 of the 862 patients without artery hyperdensity (9.9%). At 3 months, 18 patients were lost to follow-up, 325 patients (32.8%) were disabled and 165 died (16.5%). Age (OR 1.06 for 1 added year; 95% CI 1.04-1.08), National Institute of Health Stroke Scale score for 1 added point on admission (OR 1.2; 95% CI 1.2-1.3), stroke due to atherosclerosis (OR 2.3; 95% CI 1.0-5.4), hemorrhagic transformation of the ischemic lesion (OR 2.2; 95% CI 1.0-4.9), and hyperdense MCA and/or ICA (OR 2.0; 95% CI 1.0-4.0) were associated with adverse outcome., Conclusions: In this prospective cohort of patients with acute ischemic stroke, we observed an incidence of hyperdense MCA and/or ICA arteries of about 15%; hyperdense MCA and/or ICA were associated with a final infarct involving more than one third of the MCA territory and poor functional outcome at 3 months., (Copyright © 2011 S. Karger AG, Basel.)

We followed up 550 primary kidney transplant recipients in an observational retrospective cohort to evaluate the impact of three consecutive cytomegalovirus (CMV) prevention strategies. In period 1 (1996-2000; n = 190), no anti-CMV prophylaxis was given; in period 2 (2000-2004; n = 173), 6-month valacyclovir was given and in period 3 (>2004; n = 187), 6-month valganciclovir was given. Cytomegalovirus disease significantly decreased from 33.2% in period 1 to 13.9% in period 2 and to 8.6% in period 3; onset was significantly prolonged with valganciclovir (228 days) compared with valacyclovir (93 days) and with no prophylaxis (33 days). After Cox regression adjustments, both valganciclovir and valacyclovir were similarly protective factors for CMV disease. Cytomegalovirus diseases encountered in both valacyclovir and valganciclovir groups were primary infections (79.2 and 93.8% respectively) as compared with a significant low number (39.7%) in the nonprophylaxis group. Two cases of valganciclovir resistance were recorded in the valganciclovir group and no resistance was seen with valacyclovir. A significantly reduced incidence of other herpes viruses was only observed with valganciclovir. Valganciclovir was better tolerated than valacyclovir and this long-term prophylaxis was applicable to 85% of patients. Longer follow-up of valganciclovir or valacyclovir prophylaxis is still required to appreciate its impact on graft and patient survivals, as well as other indirect effects, in the mycophenolate mofetil and calcineurin inhibitor immunosuppressive era.

For more than 200 years digitalis has been considered of paramount importance in the treatment of heart failure and atrial fibrillation. The IN-CHF Italian registry shows that prescriptions were reduced from 63.3% in the period 1995-1999 to 40% in the period 2000-2005, a very different trend compared to prescriptions of angiotensin-converting enzyme inhibitors, angiotensin receptor antagonists, and beta-blockers. The commercial value of digitalis is much lower than other drugs and it does not seem to be of interest for the pharmaceutical companies. Unfortunately, this is a logical trend in the business world. For many years the major indications of digitalis have been heart failure and atrial fibrillation. The most important study on efficacy of digitalis in the treatment of heart failure was the DIG trial (1997), which showed no difference in mortality when compared to placebo but significant beneficial effects in reducing hospital admission rates. Many post-hoc researches evaluated blood levels of digitalis and proved beneficial effects also on mortality when digoxinemia values were 0.5-0.9 ng/ml. In conclusion, digitalis should still be considered effective for the treatment of heart failure; therefore prescription modality as well as the range of normal values of digoxinemia should be updated.

Spontaneous coronary artery dissection is a rare event as a cause of acute myocardial infarction. Optimal treatment remains unclear. In this report, we describe a case of spontaneous acute coronary artery dissection presenting as recurrent acute myocardial infarction in a postmenopausal woman, successfully treated with systemic thrombolysis. The case is discussed with review of the pertinent literature.